The Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Diseases Research (MRCE) is a consortium of leading Midwest institutions that will serve the biodefense research and training needs for Region VII as well as parts of Ohio. The members of the MRCE are Washington University in St. Louis (site of the administrative core), Case Western Reserve University, Cleveland Clinic/Lerner Research Institute, the University of Iowa, St. Louis University, Kansas State University, Iowa State University, the Midwest Research Institute, and the University of Missouri. The major objective of the MRCE is to harness outstanding scientists from the best institutions to focus on critical issues in biodefense and emerging infectious diseases (EID). Our goal is research that will have an immediate impact on the nation's public health, and will provide the scientific base for a strong biodefense effort. During the previous funding period the MRCE transformed biodefense and EID research in Region VII by creating a highly collaborative research program that crossed institutions and led to seminal discoveries on poxviruses, West Nile Virus and plague. The new Strategic Plan for the MRCE centers on two research themes. Each has as their ultimate goal, improved biopreparedness for Region VII and the nation. One program centers on pathogen discovery, using state of the art sequencing approaches to identify new and previously unrecognized biologic threats. This work promises to help us "know our enemy", improving our ability to develop diagnostics and therapeutics against dangerous pathogens. To help develop countermeasures to these threats, we propose to delineate, at the molecular level, how the innate immune system controls pathogenic microorganisms. Our scientists will use this information to develop ways to stimulate endogenous host defenses that can protect against multiple biological threat agents. Resources supporting the MRCE Strategic Plan include the Washington University Genome Sequencing Center, the largest sequencing center in the United States, the new University of Missouri RBL facility, and new state of the art facilities for pathogen discovery. Finally, the MRCE will lead the effort to recruit new investigators to clinical and basic research in biodefense and train them in how to conduct this research safely and securely through four distinct Career Development Programs. The MRCE is uniquely positioned to serve Region VII and the nation through an exceptional program that addresses the most immediate and urgent national biodefense needs.